Parkinson ̆s Disease (PD) is a common neurodegenerative disease, that is characterized neuropathologically by the degeneration of heterogeneous populations of neural cells (mainly dopaminergic neurons in substantia nigra) involving different neurotransmitter systems and different regions of the nervous system. The degeneration of the pigmented neurons in the pars compacta of the substantia nigra accounts for most of the distinctive motor symptoms. Neuropathological diagnosis requires the presence of eosinophilic cytoplasmatic inclusions, that is, Lewy bodies, or aggregations of misfolded synuclein in the remaining neural cells and other brain regions.
Clinical diagnosis of PD requires bradykinesia (motor impairment) and at least one of the following: resting tremor, muscular rigidity, and postural reflex impairment, which are considered the core symptoms of the disease. Misclassifications, especially in early-stage PD, occur frequently. However, around 75% of PD diagnoses will be correct, where 2 out of the 4 core symptoms are present and other neurological signs or symptoms are absent. In addition, Magnetic Resonance Imaging may be helpful for excluding other Parkinsonian syndromes. Nonetheless, in 15%-25% of the clinical diagnosis, PD cannot be confirmed histopathologically and there is an urgent need for biomarkers for PD diagnosis.
There also remains an urgent need for better treatments, for example, therapeutics that halt further neurodegeneration and delay disease progression. Nonetheless, the mechanisms responsible for the dopaminergic cell loss in PD are unknown. Moreover, no pharmacotherapy currently exists that shows a relevant delay in disease progression, as current pharmacological intervention in PD involves addressing the symptoms of PD. In particular, there remains a need for therapeutics with a pharmacology to improve PD ̆s impaired dopaminergic neurotransmission. Patients with early stages of PD may start, depending on the clinical context, with a dopamine-agonist or a dopamine precursor, such as L-Dopa. In general, a patient with early stages PD starts treatment with dopamine-agonists; if symptoms are insufficiently controlled, L-Dopa is added during the course of the disease. In advanced PD, most patients receive both L-Dopa and a dopamine-agonist.
Nonetheless, the effectiveness of L-Dopa decreases over time and non-responsive periods to this therapeutic approach increase during advanced stages of the disease. In particular, L-Dopa control of motor symptoms decreases as its efficacy wears off, and symptoms do not improve until the next dose is taken. Motor symptoms oscillate between OFF periods (medication withdrawal), which are times of decreased mobility and re-emergence of symptoms; and ON periods (after L-dopa intake), which are periods when the medication works and symptoms are controlled. With disease progression, these motor fluctuations become difficult to predict and can be dramatic in advanced PD, for patients taking high L-Dopa doses. During OFF periods, patients suffer highly impaired mobility and reduced quality of life. For example, patients taking L-Dopa for a long time and/or in high doses experience ‘OFF_ periods in L-Dopa efficacy and need therapeutic alternatives that do not further exacerbate the developing side effects.
Most of the treatments that are used as alternatives or adjuncts to L-Dopa aim to increase ON periods but none, however, whether taken alone or in combination with others, has been able to eliminate wearing off completely. The lack of alternative therapeutic options for these periods, together with an aggravation of the symptoms, are major concerns.
Studies of non-motor manifestations in patients with PD have shown that long-term L-Dopa treatment may promote the development of not only motor fluctuations, but also mood fluctuations, and significant mood changes have been found to be associated with ON/OFF phenomena in PD patients. Specific tests for anxiety and for a depressive state would provide a better and specific assessment of non-motor manifestations.
Moreover, an adverse side effect of L-Dopa is the development of motor complications during the course of the disease, following chronic use of L-Dopa. Unfortunately, however, the mechanisms leading to these motor complications are not fully understood. Most likely, the effect of L-Dopa is modified as a consequence of the continuing loss of dopaminergic cells as there is no evidence that L-Dopa itself has a deleterious effect on the PD patients disease progression. L-Dopa dose-limiting factors are believed to be the cause of involuntary movements (dyskinesias, dystonia, choreaathetosis), psychiatric side effects (e.g. hallucinations, delusions, psychosis), and autonomic side effects (e.g. orthostatic hypotension).
Current dopamine-agonists act directly on the dopamine receptors. Nonetheless, compared to L-Dopa, dopamine-agonists are relatively less effective and have a higher incidence of psychiatric and autonomic side effects. Other drug categories, such as monoamine oxidase inhibitors, catecholamine-O-methyl transferase inhibitors, anticholinergics, and glutamate modulators may represent alternative or, more often, adjunctive treatments to L-Dopa and dopamine-agonists.
There also remains an unmet need in PD regarding the symptom of ‘freezing of gait_, both from the clinician ̆s and the patient ̆s point of view. This is often a dramatic symptom, common in advanced PD, that highly impairs mobility, causes falls, and reduces quality of life. For these reasons, freezing of gait is an important clinical problem to be addressed. Nonetheless, the pathogenesis of freezing of gait is not understood and empirical treatments show poor efficacy. Non-pharmacological interventions include deep brain structures stimulation and neuronal grafts, which both have limited application. Deep brain structures stimulation is limited to highly selected patient groups; neuronal grafts mainly are investigational.
Accordingly, there remains a need in the art for therapeutics useful in treating and managing PD and related disorders, in particular, a need for therapeutics that help manage motor and non-motor symptoms during OFF periods, after chronic L-Dopa administration, and attendant motor side effects, such as problems with gait, as well as managing other conditions with associated gait problems. In particular, there remains an unmet need during advanced stages of PD, when the effectiveness of L-Dopa wears off and side effects become problematic, especially motor symptoms. There also remains an unmet need to reduce OFF periods, to make them more predictable, and to be able to continue treatment with low L-Dopa doses. Approaches that address these needs with few side effects and low risk of toxicity, even after chronic use, especially are needed. The instant invention addresses these and other needs.